Method for palladium-catalyzed cinammic acid formation

ABSTRACT

A solid-supported palladium(II) complex which catalyzes the Mizoroki-Heck coupling reaction efficiently and a method of employing the solid-supported palladium(II) complex to synthesize cinnamic acid and derivatives thereof. The solid-supported palladium(II) complex is also stable and can be recycled without significantly losing catalytic activity.

STATEMENT OF FUNDING ACKNOWLEDGEMENT

This project was funded by the National Plan for Science, Technology andInnovation (MARIFAH)-King Abdulaziz City for Science andTechnology—through the Science & Technology Unit at King Fahd Universityof Petroleum & Minerals (KFUPM), the Kingdom of Saudi Arabia, awardnumber (14-PET2737-04).

BACKGROUND OF THE INVENTION Technical Field

The present disclosure relates to a solid-supported palladium(II)complex which catalyzes the Mizoroki-Heck coupling reaction and a methodof employing the solid-supported palladium(II) complex to synthesizecinnamic acid and derivatives thereof.

Description of the Related Art

The “background” description provided herein is for the purpose ofgenerally presenting the context of the disclosure. Work of thepresently named inventors, to the extent it is described in thisbackground section, as well as aspects of the description which may nototherwise qualify as prior art at the time of filing, are neitherexpressly or impliedly admitted as prior art against the presentdisclosure.

Among metal catalysts, palladium complexes have been used widely due totheir versatility in modern organic synthesis (e.g. in synthetictransformations including Mizoroki-Heck, Suzuki, Stille and Sonogashiracross coupling reactions) (J. H. Kim, J. S. Park, H. W. Chung, B. W.Boote, T. R. Lee, RSC Adv. 2 (2012) 3968-3977; B. Tamami, H. Allahyari,S. Ghasemi, F. Farjadian, J. Organomet. Chem. 696 (2011) 594-599; A. F.Lee, P. J. Ellis, I. J. S. Fairlamb, K. Wilson, Dalton Trans. 39 (2010)10473-10482; and X. Gao, N. Zhao, M. Shu, S. Che, Appl. Catal. A: Gen.388 (2010) 196-201, each incorporated herein by reference in theirentirety).

Homogeneous palladium catalysts, however, suffer from the problemsassociated with the need and handling of sensitive ligands. Suchcatalysts are also difficult to recover and to separate from thecoupling products, making it a challenge to recycle the expensivepalladium.

The separation and recycling of homogeneous transition metal catalystsremain the most serious scientific and commercial challenges in the areaof catalysis. The difficulty in the separation and recycling processesof the transition metal catalysts has limited their practical uses forapplication in the fine chemical industry (Herrmann, W. A.; Cornils, B.Angew. Chem., Int. Ed. 1997, 36, 1048; Baker, R. T.; Tumas, W. Science1999, 284, 1477; Cole-Hamilton, D. J. Science 2003, 299, 1702; andHerrmann, W. A. Applied Homogeneous Catalysis with OrganometallicCompounds; Comils, B., Herrmann, W. A., Eds.; VCH: Weinheim, Germany,1996; Vol. 2, p 712, each incorporated herein by reference in theirentirety).

Therefore, many strategies for effective catalyst recycling have beenexplored, including supported aqueous-phase catalysis, fluorous-phasecatalysis, and the use of ionic liquids and supercritical fluids(Arhanchet, J. P.; Davis, M. E.; Merola, J. S.; Hanson, B. E. Nature1989, 339, 454; Davis, M. E. CHEMTECH 1992, 498; Sandee, A. J.; Slagt,V. F.; Reek, J. N. H.; Kamer, P. C. J.; van Leeuwen, P. W. N. M. Chem.Commun. 1999, 1633; Barthel-Rosa, L. P.; Gladysz, J. A. Coord. Chem.Rev. 1999, 190-192, 587; Rocaboy, C.; Rutherford, D.; Bennett, B. L.;Gladysz, J. A. J. Phys. Org. Chem. 2000, 13, 596; Richter, B.; Spek, A.L.; van Koten, G.; Deelman, B.-J. J. Am. Chem. Soc. 2000, 122, 3945; deWolf, E.; van Koten, G.; Deelman, B.-J. Chem. Soc. Rev.1999, 28, 37;Wasserscheid, P.; Welton, T. Ionic Liquids in Synthesis; Wiley-VCH:Weinheim, Germany, 2003; Wasserscheid, P.; Waffenschmidt, H.;Machnitzki, P.; Kottsieper, K. W.; Stelzer, O. Organometallics 2000, 19,3818; Bronger, R. P. J.; Silva, S. M.; Kamer, P. C. J.; van Leeuwen, P.W. N. M. Chem. Commun. 2002, 3044; Wasserscheid, P.; Waffenschmidt, H.;Machnitzki, P.; Kottsieper, K. W.; Stelzer, O. Chem. Commun. 2001, 451;Jessop, P. G.; Ikariya, T.; Noyori, R. Chem. Rev. 1999, 99, 475;Leitner, W. Acc. Chem. Res. 2002, 35, 746, each incorporated herein byreference in their entirety).

Hence, the support of homogeneous catalysts and the application ofsupported catalysts in fine chemical synthesis has become a major areaof research in chemistry due to the advantages of such catalysts overthe homogeneous catalysts and the positive impact on the environment(Clark, J. H.; Macquarrie, D. J. Handbook of Green Chemistry andTechnology; Blackwell: Oxford, 2002; and Anastas, P. T.; Kirchhoff, M.M.; Williamson, T. C. Appl. Catal., A 2001, 221, 3, each incorporatedherein by reference in their entirety). Therefore, there is a demand todevelop heterogeneous palladium catalysts for industrial applications.

The Mizoroki-Heck reaction is among the most important and widely usedreactions for the formation of carbon-carbon bond, which allows thearylation, alkylation or vinylation of various alkenes through theirreaction with aryl, vinyl, benzyl, or allyl halides in the presence ofpalladium and a suitable base in a single step under mild conditions(Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009;Mizoroki-Heck, R. F. Palladium Reagents in Organic Synthesis; Academic:London, 1985; Trzeciak, A. M.; Ziolkowski, J. J. Coord. Chem. Rev. 2005,249, 2308; and Alonso, F.; Beletskaya, I. P.; Yus, M. Tetrahedron 2005,61, 11771, each incorporated herein by reference in their entirety).There are some examples of the application of the Mizoroki-Heck couplingreaction on the industrial scale (Eisenstadt, A.; Ager, D. J. FineChemicals through Heterogeneous Catalysis; Sheldon, R. A., van Bekkum,H., Eds.; Wiley-VCH: Weinheim, 2001; p 576; and Zapf, A.; Beller, M.Top. Catal. 2002, 19, 101; and Tucker, C. E.; de Vries, J. G. Top.Catal. 2002, 19, 111, each incorporated herein by reference in theirentirety).

Therefore, an objective of the present disclosure is to provide asolid-supported palladium(II) catalyst effective for Mizoroki-Heckcoupling reactions. It is a further objective to provide a method ofemploying the solid-supported palladium(II) catalyst.

BRIEF SUMMARY

The foregoing paragraphs have been provided by way of generalintroduction, and are not intended to limit the scope of the followingclaims. The described embodiments, together with further advantages,will be best understood by reference to the following detaileddescription taken in conjunction with the accompanying drawings.

A first aspect of the disclosure relates to a solid-supported ligand,comprising a reaction product of:

a ligand of formula (I)

or a salt, solvate, or stereoisomer thereof, and

a solid support comprising silica,

where the solid support is functionalized to comprise a substitutedbenzyl,

a X atom in the compound of formula (I) is bonded to a carbon atom ofthe solid support,

R₁, R₂, R₃, and R₄ are independently H, an optionally substituted alkyl,an optionally substituted cycloalkyl, an optionally substitutedcycloalkylalkyl, an optionally substituted arylalkyl, an optionallysubstituted heteroaryl, an optionally substituted aryl, an optionallysubstituted heterocyclyl, an optionally substituted alkylthio, anoptionally substituted alkanoyl, an optionally substituted aroyl, anoptionally substituted heteroarylcarbonyl, an optionally substitutedhydrocarbyl, an optionally substituted arylolefin, an optionallysubstituted arylalkylcarboxylic acid, or an optionally substitutedvinyl,

each R₅ and R₆ is independently H, an optionally substituted alkyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkylalkyl, an optionally substituted arylalkyl, an optionallysubstituted heteroaryl, an optionally substituted aryl, an optionallysubstituted heterocyclyl, an optionally substituted alkylthio, anoptionally substituted alkanoyl, an optionally substituted aroyl, anoptionally substituted heteroarylcarbonyl, an optionally substitutedhydrocarbyl, an optionally substituted arylolefin, an optionallysubstituted arylalkylcarboxylic acid, or an optionally substitutedvinyl, and

n is 1 with the proviso that X is O or S, or

n is 2 with the proviso that X is N.

In one embodiment, R₁ and R₂ are CH₃, R₃, R₄, R₅, and R₆, are H, n is 1,X is O, and the solid support is silica gel.

In one embodiment, the solid support is in the form of a particle withan average diameter of 1-100 μm.

A second aspect of the disclosure relates to a solid-supported catalyst,comprising a reaction product of the solid-supported ligand of the firstaspect, and a palladium(II) salt of the formula PdZ₂, where the reactionproduct comprises a palladium(II) ion bound to a nitrogen atom in eachoxazoline heterocycle, and Z is selected from the group consisting ofCl, I, Br, OAc, and OTf.

In one embodiment, R₁ and R₂ are CH₃, R₃, R₄, R₅, and R₆ are H, n is 1,X is O, the solid support is silica gel, and Z is Cl.

In one embodiment, the solid support is in the form of a particle withan average diameter of 1-100 μm.

In one embodiment, the solid-supported catalyst comprises 0.1-1 mmol ofpalladium per gram of the solid-supported catalyst.

In one embodiment, the solid-supported catalyst has a turnover number ina range of 1,500-2,500 and a turnover frequency in a range of 200-1,500per hour.

A third aspect of the disclosure relates to a method for synthesizingcinnamic acid or derivatives thereof, the method comprising reacting anaryl halide with an acrylic acid or derivatives thereof in the presenceof a solvent, a base, and the solid-supported catalyst of the secondaspect at a temperature in a range of 35-110° C., thereby forming thecinnamic acid or derivatives thereof.

In one embodiment, the method further comprises separating thesolid-supported catalyst from the cinnamic acid or derivatives thereof,and reusing the solid-supported catalyst in at least two cycles, wherethe solid-supported catalyst loses less than 5 wt % of the palladiumafter the at least two cycles.

In one embodiment, the aryl halide is a limiting reactant.

In one embodiment, an amount of the solid-supported catalyst is in arange of 0.05-10 mol % relative to a number of moles of the aryl halide.

In one embodiment, the solvent comprises 5-95% by volume of water and5-95% by volume of an organic solvent, based on a total volume of thesolvent.

In one embodiment, the organic solvent is dimethyl formamide.

In one embodiment, the base is at least one selected from the groupconsisting of an alkali metal hydroxide, an alkali metal carbonate, andan amine.

In one embodiment, the cinnamic acid or derivatives thereof comprisesless than 10 ppb palladium, based on a total weight of the cinnamic acidor derivatives thereof.

A fourth aspect of the disclosure relates to a method for synthesizingcinnamic acid or derivatives thereof, the method comprising reacting anaryl halide with an acrylic acid or derivatives thereof in the presenceof a solvent, a base, and the solid-supported catalyst of the secondaspect with R₁ and R₂ are CH₃, R₃, R₄, R₅, and R₆ are H, X is O, SS issilica gel, and Z is Cl at a temperature in a range of 35-110° C.,thereby forming the cinnamic acid or derivatives thereof.

In one embodiment, the method further comprises separating thesolid-supported catalyst from the cinnamic acid or derivatives thereof,and reusing the solid-supported catalyst in at least two cycles, whereinthe solid-supported catalyst loses less than 5 wt % of the palladiumafter the at least two cycles.

In one embodiment, the cinnamic acid or derivatives thereof comprisesless than 10 ppb palladium, based on a total weight of the cinnamic acidor derivatives thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

A more complete appreciation of the disclosure and many of the attendantadvantages thereof will be readily obtained as the same becomes betterunderstood by reference to the following detailed description whenconsidered in connection with the accompanying drawings, wherein:

FIG. 1 is an overlay of the FT-IR spectra of unmodified 4-benzylchloride functionalized silica support “Silica Support”,silica-supported BOX ligand “BOX—Si”, silica-supported Pd-BOX catalyst“Fresh Pd-BOX—Si”, and used silica-supported Pd-BOX catalyst “UsedPd-BOX—Si” recovered from Mizoroki-Heck coupling reaction.

FIG. 2 is a cross-polarization magic angle spinning (CP-MAS) ¹³C NMRspectrum of the silica-supported BOX ligand.

FIG. 3 is a CP-MAS ¹³C NMR spectrum of the silica-supported Pd-BOXcatalyst.

FIG. 4 is an overlay of thermogravimetric curves of the silica-supportedBOX ligand “BOX—Si” and the silica-supported Pd-BOX catalyst“Pd-BOX—Si”.

FIG. 5 is a scanning electron micrograph of the unmodified 4-benzylchloride functionalized silica support.

FIG. 6 is a scanning electron micrograph of the silica-supported BOXligand.

FIG. 7 is a scanning electron micrograph of the silica-supported Pd-BOXcatalyst.

FIG. 8 is a XPS spectrum of the fresh silica-supported Pd-BOX catalyst,showing Pd 3d.

FIG. 9 is a XPS spectrum of the used silica-supported Pd-BOX catalyst,showing Pd 3d.

FIG. 10 is a graph showing the isolated yields of cinnamic acid formedin the presence of recycled silica-supported Pd-BOX catalyst, which wasrecycled after each run and used in the subsequent run.

DETAILED DESCRIPTION OF THE EMBODIMENTS

Embodiments of the present disclosure will now be described more fullyhereinafter with reference to the accompanying drawings, in which some,but not all of the embodiments of the disclosure are shown.

The present disclosure will be better understood with reference to thefollowing definitions.

As used herein, the words “a” and “an” and the like carry the meaning of“one or more”.

As used herein, the terms “compound”, “complex”, and “catalyst” are usedinterchangeably, and are intended to refer to a chemical entity, whetherin the solid, liquid or gaseous phase, and whether in a crude mixture orpurified and isolated. As used herein, the term “ligand” refers to anorganic molecule comprising at least a phenyl ring, and two oxazolinegroups bound separately to the phenyl ring via a C—C bond and arrangedortho to one another, and each oxazoline group comprises a nitrogen atomwhich can bind to the palladium(II) ion covalently thereby forming achelate.

The term “alkyl”, as used herein, unless otherwise specified, refers toa straight, branched, or cyclic hydrocarbon fragment. Non-limitingexamples of such hydrocarbon fragments include methyl, ethyl, propyl,isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl,hexyl, isohexyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl,vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl,1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl,3-hexenyl, 4-hexenyl, or 5-hexenyl. As used herein, the term “cyclichydrocarbon” refers to a cyclized alkyl group. Exemplary cyclichydrocarbon (i.e. cycloalkyl) groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, andadamantyl. Branched cycloalkyl groups, such as exemplary1-methylcyclopropyl and 2-methycyclopropyl groups, are included in thedefinition of cycloalkyl as used in the present disclosure.

The term “aryl”, as used herein, and unless otherwise specified, refersto phenyl, biphenyl, naphthyl, anthracenyl, and the like. The term“heteroaryl” refers to an aryl group where at least one carbon atom isreplaced with a heteroatom (e.g. nitrogen, oxygen, sulfur) and can beindolyl, furyl, imidazolyl, triazolyl, triazinyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, pyrazolyl, pyrrolyl, pyrazinyl, tetrazolyl,pyridyl (or its N-oxide), thienyl, pyrimidinyl (or its N-oxide),1H-indolyl, isoquinolyl (or its N-oxide), or quinolyl (or its N-oxide),for example.

As used herein, the term “substituted” refers to at least one hydrogenatom that is replaced with a non-hydrogen group, provided that normalvalencies are maintained and that the substitution results in a stablecompound. When a compound or a R group (denoted as R₁, R₂, and so forth)is noted as “optionally substituted”, the substituents are selected fromthe exemplary group including, but not limited to, aroyl (as definedhereinafter), halogen (e.g. chlorine, bromine, fluorine or iodine),alkyl, alkoxy (i.e. straight or branched chain alkoxy having 1 to 10carbon atoms, and includes, for example, methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, secondary butoxy, tertiary butoxy,pentoxy, isopentoxy, hexyloxy, heptyloxy, octyloxy, nonyloxy anddecyloxy), cycloalkyloxy including cyclopentyloxy, cyclohexyloxy, andcycloheptyloxy, aryloxy including phenoxy and phenoxy substituted withhalo, alkyl, alkoxy, and haloalkyl which refers to straight or branchedchain alkyl having 1 to 8 carbon atoms which are substituted by at leastone halogen, and includes, for example, chloromethyl, bromomethyl,fluoromethyl, iodomethyl, 2-chloroethyl, 2-bromoethyl, 2-fluoroethyl,3-chloropropyl, 3-bromopropyl, 3-fluoropropyl, 4-chlorobutyl,4-fluorobutyl, dichloromethyl, dibromomethyl, difluoromethyl,diiodomethyl, 2,2-dichloroethyl, 2,2-dibromoethyl, 2,2-difluoroethyl,3,3-dichloropropyl, 3,3-difluoropropyl, 4,4-dichlorobutyl,4,4-difluorobutyl, trichloromethyl, trifluoromethyl,2,2,2-tri-fluoroethyl, 2,3,3-trifluoropropyl, 1,1,2,2-tetrafluoroethyl,2,2,3,3-tetrafluoropropyl, hydrocarbyl, substituted hydrocarbyl,arylalkyl, hydroxy, alkoxy, oxo, alkanoyl, alkanoyloxy, amino,alkylamino, arylamino, arylalkylamino, disubstituted amines (e.g. inwhich the two amino substituents are selected from the exemplary groupincluding, but not limited to, alkyl, aryl, or arylalkyl), alkanylamino,arylamino, alkanoylamino, substituted alkanoylamino, substitutedarylamino, substituted arylamino, thiol, alkylthio, arylthio,arylalkylthio, alkylthiono, arylthiono, aryalkylthiono, alkylsulfonyl,arylsulfonyl, arylalkylsulfonyl, sulfonamido (e.g. —SO₂NH₂), substitutedsulfonamide, nitro, cyano, carboxy, carbamyl (e.g. —CONH₂), substitutedcarbamyl (e.g. —CONHalkyl, —CONHaryl, —CONHarylalkyl or cases wherethere are two substituents on one nitrogen from alkyl, aryl, orarylalkyl), alkoxycarbonyl, aryl, substituted aryl, guanidine,heteroarylcarbonyl, substituted heteroarylcarbonyl, heterocyclyl,substituted heterocyclyl and mixtures thereof and the like. Thesubstituents may be either unprotected, or protected as necessary, asknown to those skilled in the art, for example, as taught in Greene, etal., “Protective Groups in Organic Synthesis”, John Wiley and Sons,Second Edition, 1991, hereby incorporated by reference in its entirety).

The term “heterocyclyl” as used in this disclosure refers to a 3-8,preferably 4-8, more preferably 4-7 membered monocyclic ring or a fused8-12 membered bicyclic ring which may be saturated or partiallyunsaturated, which monocyclic or bicyclic ring contains 1 to 4heteroatoms selected from oxygen, nitrogen, silicon or sulfur. Examplesof such monocyclic rings include oxaziridinyl, homopiperazinyl,oxiranyl, dioxiranyl, aziridinyl, pyrrolidinyl, azetidinyl,pyrazolidinyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl,thiomorpholinyl, thiazolidinyl, hydantoinyl, valerolactamyl, oxiranyl,oxetanyl, dioxolanyl, dioxanyl, oxathiolanyl, oxathianyl, dithianyl,dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl,tetrahydropyridyl, tetrahydropyrimidinyl, tetrahydrothiophenyl,tetrahydrothiopyranyl, diazepanyl and azepanyl. Examples of suchbicyclic rings include indolinyl, isoindolinyl, benzopyranyl,quinuclidinyl, 2,3,4,5-tetrahydro-1,3,benzazepine,4-(benzo-1,3,dioxol-5-methyl)piperazine, and tetrahydroisoquinolinyl.Further, “substituted heterocyclyl” may refer to a heterocyclyl ringwhich has one or more oxygen atoms bonded to the ring (i.e. as ringatoms). Preferably, said atom which is bonded to the ring selected fromnitrogen or sulphur. An example of a heterocyclyl substituted with oneor more oxygen atoms is 1,1-dioxido-1,3-thiazolidinyl.

The term “alkylthio” as used in this disclosure refers to a divalentsulfur with alkyl occupying one of the valencies and includes the groupsmethylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio,octylthio.

The term “alkanoyl” as used in this disclosure refers to an alkyl grouphaving 2 to 18 carbon atoms that is bound with a double bond to anoxygen atom. Examples of alkanoyl includes, acetyl, propionyl, butyryl,isobutyryl, pivaloyl, valeryl, hexanoyl, octanoyl, lauroyl, stearoyl.

The term “arylalkyl” as used in this disclosure refers to a straight orbranched chain alkyl moiety having 1 to 8 carbon atoms that issubstituted by an aryl group or a substituted aryl group having 6 to 12carbon atoms, and includes benzyl, 2-phenethyl, 2-methylbenzyl,3-methylbenzyl, 4-methylbenzyl, 2,4-dimethylbenzyl,2-(4-ethylphenyl)ethyl, 3-(3-propylphenyl)propyl.

Examples of aroyl are benzoyl and naphthoyl, and “substituted aroyl” mayrefer to benzoyl or naphthoyl substituted by at least one substituentincluding those selected from halogen, amino, vitro, hydroxy, alkyl,alkoxy and haloalkyl on the benzene or naphthalene ring.

The term “heteroarylcarbonyl” as used in this disclosure refers to aheteroaryl moiety with 5 to 10 membered mono- or fused- heteroaromaticring having at least one heteroatom selected from nitrogen, oxygen andsulfur as mentioned above, and includes, for example, furoyl,nicotinoyl, isonicotinoyl, pyrazolylcarbonyl, imidazolylcarbonyl,pyrimidinylcarbonyl, benzimidazolyl-carbonyl. Further, “substitutedheteroarylcarbonyl” may refer to the above mentioned heteroarylcarbonylwhich is substituted by at least one substituent selected from halogen,amino, vitro, hydroxy, alkoxy and haloalkyl on the heteroaryl nucleus,and includes, for example, 2-oxo-1,3-dioxolan-4-ylmethyl,2-oxo-1,3-dioxan-5-yl.

Vinyl refers to an unsaturated substituent having at least oneunsaturated double bond and having the formula CH₂═CH—. Accordingly,said “substituted vinyl” may refer to the above vinyl substituent havingat least one of the protons on the terminal carbon atom replaced withalkyl, cycloalkyl, cycloalkylalkyl, aryl, substituted aryl, heteroarylor substituted heteroaryl.

The term “hydrocarbyl” as used herein refers to a univalent hydrocarbongroup containing up to about 24 carbon atoms (i.e., a group containingonly carbon and hydrogen atoms) and that is devoid of olefinic andacetylenic unsaturation, and includes alkyl, cycloalkyl,alkyl-substituted cycloalkyl, cycloalkyl-substituted cycloalkyl,cycloalkylalkyl, aryl, alkyl-substituted aryl, cycloalkyl-substitutedaryl, arylalkyl, alkyl-substituted aralkyl, and cycloalkyl-substitutedaralkyl. Further, functionally-substituted hydrocarbyl groups may referto a hydrocarbyl group that is substituted by one or more functionalgroups selected from halogen atoms, amino, nitro, hydroxy,hydrocarbyloxy (including alkoxy, cycloalkyloxy, and aryloxy),hydrocarbylthio (including alkylthio, cycloalkylthio, and arylthio),heteroaryl, substituted heteroaryl, alkanoyl, aroyl, substituted aroyl,heteroarylcarbonyl, and substituted heteroarylcarbonyl.

As used herein, the term “derivative” refers to a chemically modifiedversion of a chemical compound that is structurally similar to a parentcompound.

The present disclosure is further intended to include all isotopes ofatoms occurring in the present compounds. Isotopes include those atomshaving the same atomic number but different mass numbers. By way ofgeneral example, and without limitation, isotopes of hydrogen includedeuterium and tritium. Isotopes of carbon include ¹³C and ¹⁴C.Isotopically labeled compounds of the disclosure can generally beprepared by conventional techniques known to those skilled in the art orby processes and methods analogous to those described herein, using anappropriate isotopically labeled reagent in place of the non-labeledreagent otherwise employed.

As used herein, the term “solvent” includes, but is not limited to,water (e.g. tap water, distilled water, doubly distilled water,deionized water, deionized distilled water), organic solvents, such asethers (e.g. diethyl ether, tetrahydrofuran, 1,4-dioxane,tetrahydropyran, t-butyl methyl ether, cyclopentyl methyl ether,di-iso-propyl ether), glycol ethers (e.g. 1,2-dimethoxyethane, diglyme,triglyme), alcohols (e.g. methanol, ethanol, trifluoroethanol,n-propanol, i-propanol, n-butanol, i-butanol, t-butanol, n-pentanol,i-pentanol, 2-methyl-2-butanol, 2-trifluoromethyl-2-propanol,2,3-dimethyl-2-butanol,3-pentanol, 3-methyl-3-pentanol,2-methyl-3-pentanol, 2-methyl-2-pentanol, 2,3-dimethyl-3-pentanol,3-ethyl-3-pentanol, 2-methyl-2-hexanol, 3-hexanol, cyclopropylmethanol,cyclopropanol, cyclobutanol, cyclopentanol, cyclohexanol), aromaticsolvents (e.g. benzene, o-xylene, m-xylene, p-xylene, and mixtures ofxylenes, toluene, mesitylene, anisole, 1,2-dimethoxybenzene,α,α,α,-trifluoromethylbenzene, fluorobenzene), chlorinated solvents(e.g. chlorobenzene, dichloromethane, 1,2-dichloroethane,1,1-dichloroethane, chloroform), ester solvents (e.g. ethyl acetate,propyl acetate), amide solvents (e.g. dimethylformamide,dimethylacetamide, N-methyl-2-pyrrolidone), urea solvents, ketones (e.g.acetone, butanone), acetonitrile, propionitrile, butyronitrile,benzonitrile, dimethyl sulfoxide, ethylene carbonate, propylenecarbonate, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, andmixtures thereof.

As used herein, the term “base” includes, but is not limited to, analkali metal hydride (e.g. sodium hydride, potassium hydride), an alkalimetal hydroxide (e.g. lithium hydroxide, potassium hydroxide, sodiumhydroxide, cesium hydroxide), an alkali metal carbonate (e.g. lithiumcarbonate, potassium carbonate, sodium carbonate, cesium carbonate), analkali metal acetate (e.g. lithium acetate, sodium acetate, potassiumacetate), an amine (e.g. trialkylamine of formula NR′₃ (where each R′may be independently ethyl, n-propyl, and n-butyl) and dialkylamine offormula HNR′₂, or mixtures thereof, diethylamine, di-n-butylamine,pyrrolidine, piperidine, triethylamine, tri-n-butylamine,diisopropylethylamine, dicyclohexylmethylamine, pyridine,2,6-dimethylpyridine, 4-aminopyridine,N-methyl-2,2,6,6-tetramethylpiperidine, 2,2,6,6-tetramethylpiperidine,2,6-di-tert-butylpyridine, 1,4-diazabicyclo[2.2.2]octane), and mixturesthereof. The presence of a base is often important for thepalladium-catalyzed Mizoroki-Heck coupling reaction in order toneutralize the hydrogen halide produced as the byproduct of the couplingreaction (Chih-chung, T.; Mungyuen, L.; Bingli, M.; Sarah, W.; Alan, S.C.; Chem. Lett. 2011, 40:9 955. Thorwirth, R.; Stolle, A.; Ondruschka,B.; Green Chem. 2010, 12, 985. Bakherad, M.; Keivanloo, A.; Samangooei,S.; Omidian, M. J. Organometal. Chem. 2013, 740, 78. Feng, Z.; Yu, S.;Shang, Y. Appl. Organometal. Chem. 2008, 22, 577. Shingo, A.; Motohiro,S.; Yuki, S.; Hirojiki, S.; Takuya, Y.; Aiky, O. Chem. Lett. 2011, 40:9,925. Korzec, M.; Bartczak, P.; Niemczyk, A.; Szade, J.; Kapkowski, M.;Zenderowska, P.; Balin, K.; Lelarko, J.; Polariski, J. J. Catal. 2014,313, 1. Zhang, G.; Luan, Y.; Han, X.; Wang, Y.; Wen, X.; Ding, C. Appl.Organometal. Chem. 2014, 28, 332, each incorporated herein by referencein their entirety).

As used herein, the term “palladium(II) salt” includes, but is notlimited to, palladium(II) chloride, palladium(II) bromide, palladium(II)iodide, bis(benzonitrile) palladium(II) chloride,bis(acetonitrile)palladium(II) chloride, and palladium(II) acetate.

A first aspect of the disclosure relates to a solid-supported ligand,comprising a reaction product of:

a ligand of formula (I)

or a salt, solvate, or stereoisomer thereof, and

a solid support comprising silica,

where the solid support may be functionalized to comprise a substitutedbenzyl, a X atom in the compound of formula (I) is bonded to a carbonatom of the solid support, and n is 1 with the proviso that X is O or S,or n is 2 with the proviso that X is N.

The solid support functionalized with an optionally substituted benzylmay be represented by the following formula:

where SS is the solid support, and W may be Cl, Br, or I.

The solid-supported ligand may be represented by the following formula:

where m is 1 with the proviso that X is N, or m=0 (i.e. no H) with theproviso that X is O or S.

Substituents R₁, R₂, R₃, and R₄ may be independently H, an optionallysubstituted alkyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkylalkyl, an optionally substituted arylalkyl, anoptionally substituted heteroaryl, an optionally substituted aryl, anoptionally substituted heterocyclyl, an optionally substitutedalkylthio, an optionally substituted alkanoyl, an optionally substitutedaroyl, an optionally substituted heteroarylcarbonyl, an optionallysubstituted hydrocarbyl, an optionally substituted arylolefin, anoptionally substituted arylalkylcarboxylic acid, or an optionallysubstituted vinyl.

Each R₅, R₆, and R₇ may be independently H, an optionally substitutedalkyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkylalkyl, an optionally substituted arylalkyl, an optionallysubstituted heteroaryl, an optionally substituted aryl, an optionallysubstituted heterocyclyl, an optionally substituted alkylthio, anoptionally substituted alkanoyl, an optionally substituted aroyl, anoptionally substituted heteroarylcarbonyl, an optionally substitutedhydrocarbyl, an optionally substituted arylolefin, an optionallysubstituted arylalkylcarboxylic acid, or an optionally substitutedvinyl.

The optionally substituted alkyl group may comprise 1-8 carbon atoms,preferably 1-5 carbon atoms, more preferably 1-3 carbon atoms. In oneembodiment, the optionally substituted alkyl group comprises 1 carbonatom and is a methyl group. The optionally substituted aryl group ispreferably a phenyl group. The alkyl and aryl groups may be substitutedwith the aforementioned substituents. Preferably, the alkyl and/or thearyl groups are substituted with hydroxyl, alkoxy, aryloxy, nitro, orcyano, either unprotected, or protected as necessary.

In another embodiment, R₁, R₂, R₃, R₄, R₅, R₆, and R₇ may beindependently a halogen atom, a hydroxyl, a nitro, a cyano, anoptionally substituted heterocyclyl, an optionally substitutedarylalkyl, an optionally substituted heteroaryl, or an optionallysubstituted alkoxyl. The optionally substituted heterocyclyl may be aderivative of an O-heterocyclyl such as tetrahydrofuran,tetrahydropyran, or dioxane. The optionally substituted heteroaryl maybe a derivative of an O-heteroaromatic compound such as furan. Theoptionally substituted arylalkyl may be, but is not limited to, benzyl,phenethyl, and phenylpropyl. The optionally substituted alkoxyl may be,but is not limited to, methoxy, ethoxy, and phenoxyl.

In some embodiments, R₁ and R₂ may not be an amino, an alkylamino, anarylamino, a N-monosubstituted amino, a N,N-disubstituted amino, a thiolor an optionally substituted thioalkoxyl because these groups containnucleophilic atoms that may poison the catalyst. As used herein, theterm “poisoning” refers to the nucleophilic atom(s) coordinatingstrongly to the palladium ion and thereby reducing the effectiveness ofthe catalyst.

The recycling of homogeneous catalysts is complex and costly. Therefore,the use of immobilized catalysts is a good option for industries tocombine the advantages of both homogeneous and heterogeneous catalystsand also to overcome the problem related to metal contamination(Polshettiwar, V.; Len, C.; Fihri, A. Coord. Chem. Rev. 2009, 253, 2599;Hallamn, K.; Moberg, C. Tetrahedron: Asymmetry, 2001, 12, 1475,incorporated herein by reference in its entirety).

The solid support may be in a form of a particle with a shape of asphere, ellipsoid, cube, cuboid, cylindrical, or polygonal prism (e.g.triangular prism, hexagonal prism, and pentagonal prism). In a preferredembodiment, the solid support particle has an irregular shape. Anaverage diameter of the solid support particle may be in a range of1-100 μm, preferably 20-80 μm, more preferably 35-75 μm. In otherembodiments, the average diameter of the solid support particle is in arange of 0.5-1,000 nm, preferably 1-500 nm, more preferably 5-100 nm.For spherical, ellipsoidal, or irregularly-shaped particles, the term“diameter” refers to a longest straight-line distance between two pointson a surface of the particle. A surface area of the solid supportparticle may range from 100-2,000 m²/g, preferably 300-1,000 m²/g, morepreferably 500-1,000 m²/g. The solid support particle may comprise poreswith an average diameter in a range of 0.5-50 nm, preferably 0.5-30 nm,more preferably 0.5-10 nm. A porosity of the solid support may be in arange of 1-99%, preferably 20-90%, more preferably 40-80%. In oneembodiment, the solid support is non-porous.

The solid support may comprise at least 10 wt %, preferably at least 50wt %, more preferably at least 70 wt % silica, more preferably at least80 wt % silica, more preferably at least 90 wt % silica, more preferablyat least 95 wt % silica, more preferably at least 99 wt % silica, basedon a total weight of the solid support. Exemplary solid supportincludes, without limitation, zeolite/aluminum silicate (e.g.andalusite, kyanite, sillimanite, kaolinite, metakaolinite, 3:2 mullite,2:1 mullite), amorphous silica, crystalline silica, fibrous silica,precipitated silica, mesoporous silica (e.g. MCM-41 and SBA-15), fumedsilica, silica-alumina, and silica gel.

The solid support may be functionalized to facilitate a covalentattachment of the ligand. The term “functionalize” refers to themodification of a surface of the solid support particle with an organicmoiety containing carbon. Exemplary organic moiety includes, withoutlimitation, 4-benzyl chloride, 3-aminopropyl, 4-bromopropyl,4-bromophenyl, 3-carboxypropyl, 2-(carbomethoxy)propyl, 3-chloropropyl,3-(2-succinic anhydride)propyl, 1-(allyl)methyl, 3-(thiocyano)propyl,3-(isocyano)propyl, propionyl chloride, 3-(maleimido)propyl,3-(glycidoxy)propyl, 4-ethyl benzenesulfonyl chloride,2-(3,4-epoxycyclohexyl)propyl, and 3-propylsulfonic acid, preferably4-benzyl chloride. A loading of the organic moiety on the solid supportmay be in a range of 1-10 mmol/g, preferably 1-5 mmol/g, more preferably1-3 mmol/g.

In a preferred embodiment, R₁ and R₂ are CH₃, R₃, R₄, R₅, R₆, and R₇ areH, m is 0, X is O, and the solid support (or SS) is silica gel.

A preparation of the precursor to the ligand is described hereinafter. Asolution of 4-halophthalonitrile of the following structure:

where Y is I, Br, or Cl, preferably I, and a triflate salt (e.g. zinctriflate) in dried chlorobenzene is stirred at room temperature for 15min. An amount of 4-halophthalonitrile is in a range of 1-20 mmol,preferably 1-10 mmol, more preferably 1-5 mmol. In some embodiments,other triflate salts such as lanthanide triflates of the formulaLn(OTf)₃ (where Ln=La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb,Lu, Y) and scandium triflate are used. An amount of triflate salt is ina range of 0.1-1 mmol, preferably 0.1-0.5 mmol, more preferably 0.1-0.3mmol, and 1-10 mol % relative to the number of moles of the4-halophthalonitrile, preferably 1-8 mol %, more preferably 3-6 mol %.Preferred organic solvents include, without limitation, benzene,toluene, p-xylene, o-xylene, and m-xylene. An amount of the organicsolvent is in a range of 5-50 ml, preferably 10-40 ml, more preferably20-40 ml. The solution may be stirred for 5-60 minutes, preferably 5-30minutes, more preferably 10-20 minutes at a temperature in a range of10-40° C., preferably 15-30° C., more preferably 20-30° C.

A solution of a β-amino alcohol of the following structure:

in dried chlorobenzene may be added to the solution of4-halophthalonitrile and triflate salt in dried chlorobenzene to form areaction mixture. An amount of the β-amino alcohol is in a range of 1-40mmol, preferably 1-30 mmol, more preferably 1-15 mmol, and a molar ratioof 2-amino-1-propanol to 4-halophthalonitrile is in a range of 1:1 to20:1, preferably 1:1 to 10:1, more preferably 1:1 to 5:1. The β-aminoalcohol may be further substituted and comprise the aforementionedsubstituents on C-1, C-2, or both, and may be a chiral reagent, anachiral reagent, or a racemic mixture. Preferably, an achiral2-amino-2-methyl-1-propanol is used. In other embodiments, a chiralligand is prepared by employing only one of the enantiomers of2-amino-1-propanol (or further substituted 2-amino-1-propanol), such as(S)-(+)-2-amino-1-propanol or (R)-(−)-2-amino-1-propanol.

The temperature of the reaction mixture may be raised to 80-160° C.,preferably 100-160° C., more preferably 110-140° C. and may be refluxedfor 12-48 hours, preferably 18-48 hours, more preferably 18-36 hours.The precursor to the ligand may be isolated and purified by methodsknown to those skilled in the art, such as filtration through a celitecontaining cartridge, aqueous work-up, extraction with organic solvents,distillation, crystallization, column chromatography, and high pressureliquid chromatography (HPLC) on normal phase or reversed phase.Preferred methods include, extraction with organic solvents and columnchromatography, but are not limited to those exemplified. The yield ofthe precursor is at least 50%, preferably at least 75%, more preferablyat least 80%.

A preparation of the ligand is described hereinafter. The precursor tothe ligand, a palladium(II) salt, a base, and an arylboronic acid or anarylboronic ester may be added to a solvent and heated to a temperaturein a range of 50-150° C., preferably 60-100° C., more preferably 60-80°C. for 1-48 hours, preferably 1-24 hours, more preferably 1-10 hours.Preferably, the palladium(II) salt is palladium(II) chloride, the baseis potassium carbonate, and the solvent may comprise water, alcohol,toluene, dimethyl formamide, tetrahydrofuran, acetone, or mixturesthereof. Preferably, the solvent is a mixture consisting of dimethylformamide and water and comprises 10-50 vol %, preferably 30-50 vol %,more preferably 40-50 vol % of water, based on a total volume of thesolvent. A volume of the solvent may be in a range of 1-20 ml,preferably 1-10 ml, more preferably 1-5 ml. The arylboronic acid/estercomprises a hydroxy, amine, or a thiol substituent and may be furthersubstituted with the aforementioned substituents (e.g. R₆). Preferably,the arylboronic acid/ester is 4-hydroxy phenylboronic acid. An amount ofthe precursor to the ligand may be in a range of 0.1-10 mmol, preferably0.1-3 mmol, more preferably 0.1-1 mmol. An amount of the palladium(II)salt may be in a range of 1-20 mol %, preferably 1-10 mol %, morepreferably 4-6 mol %, based on the number of moles of the precursor tothe ligand. An amount of the base may be in a range of 1-10 molarequivalents, more preferably 1-5 molar equivalents, more preferably 1-3molar equivalents of the amount of the precursor to the ligand. Anamount of the arylboronic acid may be in a range of 1-10 molarequivalents, more preferably 1-2 molar equivalents, more preferably1-1.5 molar equivalents of the amount of the precursor to the ligand.The ligand may be isolated and purified by methods known to thoseskilled in the art, such as filtration through a celite containingcartridge, aqueous work-up, extraction with organic solvents,distillation, crystallization, column chromatography, and high pressureliquid chromatography (HPLC) on normal phase or reversed phase. Theyield of the ligand is at least 50%, preferably at least 75%, morepreferably at least 80%.

A preparation of the solid-supported ligand of formula (I) is describedhereinafter. A base may be added to a solution of the ligand in a dryorganic solvent to form a mixture which is stirred for 1-10 hours,preferably 1-5 hours, more preferably 1-3 hours at a temperature in arange of 15-50° C., preferably 20-40° C., more preferably 20-30° C.under an inert atmosphere provided by nitrogen gas, helium gas, argongas, or mixtures thereof. An amount of the ligand may range from 0.1-5mmol, preferably 0.1-1 mmol, more preferably 0.1-0.5 mmol. An amount ofthe base may be in a range of 1-10 molar equivalents, more preferably1-5 molar equivalents, more preferably 1-2 molar equivalents of theamount of the ligand. Preferably, the base is sodium hydride. The solidsupport particle is then added to the mixture and then stirred at atemperature in a range of 40-150° C., preferably 40-100° C., morepreferably 80-100° C. for 1-96 hours, preferably 1-48 hours, morepreferably 10-20 hours. The solid-supported ligand may be isolated andpurified by methods known to those skilled in the art, such asfiltration through a celite containing cartridge. The solid-supportedligand may also be washed with solvents, such as methanol, water,acetone, and dichloromethane, and dried under reduced pressure (e.g.0.1-50 mbar, preferably 0.1-10 mbar, more preferably 0.1-1 mbar).

A second aspect of the disclosure relates to a solid-supported catalyst,comprising a reaction product of the solid-supported ligand of the firstaspect, and a palladium(II) salt of the formula PdZ₂, where the reactionproduct comprises a palladium(II) ion bound to a nitrogen atom in eachoxazoline heterocycle of the ligand of formula (I), and Z is selectedfrom the group consisting of Cl, I, Br, OAc, and OTf. The catalyst maybe represented by the following formula (II):

where m is 1 with the proviso that X is N, or m is 0 (i.e. no H) withthe proviso that X is O or S.

In a preferred embodiment, R₁ and R₂ are CH₃, R₃, R₄, R₅, R₆, and R₇ areH, m is 0, X is O, the solid support (or SS) is silica gel, and Z is Cl.

The solid-supported catalyst comprises 0.1-1 mmol, preferably 0.1-0.6mmol, more preferably 0.1-0.4 mmol of palladium per gram ofsolid-supported catalyst. The amount of palladium in the solid-supportedcatalyst may be determined by elemental analysis or inductively coupledplasma mass spectrometry (ICP-MS). The solid-supported catalyst has aturnover number in a range of 1,500-2,500, preferably 1,500-2,000, morepreferably 1,700-2,000 and a turnover frequency in a range of 200-1,500per hour, preferably 200-1,000 per hour, more preferably 200-500 perhour. The aforementioned values of turnover number and turnoverfrequency of the solid-supported catalyst may be observed when thesolid-supported catalyst catalyzes any coupling reaction such asMizoroki-Heck, Mizoroki-Heck-Matsuda, Sonogashira, Kumada, Negishi,Stille, Suzuki, Hiyama, and Buchwald-Hartwig.

A preparation of the solid-supported palladium(II) complex of formula(II) is described hereinafter. The solid-supported ligand may besuspended and stirred in a dry organic solvent (e.g. toluene, benzene,dimethyl sulfoxide, tetrahydrofuran, or mixtures thereof) for 5-120minutes, preferably 5-90 minutes, more preferably 10-60 minutes. Anamount of the ligand is in a range of 0.1-5 mmol, preferably 0.1-3 mmol,more preferably 0.1-1 mmol. A solution of a palladium(II) salt in thesame solvent is added to the solid-supported ligand and the resultingmixture may be stirred at a temperature in a range of 40-150° C.,preferably 40-100° C., more preferably 80-100° C. for 1-96 hours,preferably 1-48 hours, more preferably 10-20 hours. A molar ratio of theligand to the palladium(II) salt is in a range of 1:1 to 1:2, preferably1:1 to 2:3, more preferably 1:1 to 1:1.2. The solid-supported catalystmay also be washed with solvents, such as ethanol, methanol, water,acetone, and dichloromethane, and dried under reduced pressure (e.g.0.1-50 mbar, preferably 0.1-10 mbar, more preferably 0.1-1 mbar).

This disclosure relates to a solid-supported palladium(II) complex forthe Mizoroki-Heck coupling reactions of halides (e.g. aryl halide,benzyl halide, or vinyl halide with the halide being Cl, Br, I),triflates (e.g. aryl triflate, benzyl triflate, or vinyl triflate), ortosylates (aryl tosylate, benzyl tosylate, or vinyl tosylate) with anacrylic acid or derivatives thereof. Preferably, the solid-supportedcatalyst system tolerates a variety of functional groups on the halideand/or the acrylic acid and derivatives thereof. That is, thesolid-supported catalyst retains the aforementioned turnover number andturnover frequency regardless of the functional groups on the halidesand/or the acrylic acid and derivatives thereof. Exemplary halides,triflates, and tosylates include, without limitation,1-bromonaphthalene, 2-bromonaphthalene, bromobenzene, 4-bromoanisole,4-bromotoluene, 1-bromo-4-fluorobenzene, 2-bromoanisole,N-methyl-2-bromopyrrole, 3-bromoindole,5-bromo-2-methyl-1,3-benzothiazole, 3-bromobenzofuran,3-bromobenzothiophene, 2-bromothiophene, 2-bromothiophene,4-bromo-3-chromene, 1-bromostyrene and (E)-2-bromostyrene,1-bromocyclohexene, 1-bromocyclopentene, bromoethene,(E)-1-bromopropene, 2-bromopropene, iodobenzene, 1-iodonaphthalene,2-iodonaphthalene, 4-iodoanisole, 4-iodotoluene, 4-chlorotoluene,2-chlorotoluene, l-chloronaphthalene, 2-chloronaphthalene,chlorobenzene, 4-chloroanisole, 2-chloroanisole, 3-chloroindole,N-methyl-2-chloropyrrole, 5-chloro-1,3-benzothiazole,3-chlorobenzofuran, 3-chlorobenzothiophene, 2-chlorothiophene,2-chlorothiophene, phenyl tosylate, allyl tosylate, 1-naphthyl tosylate,2-naphthyl tosylate, phenyl tosylate, p-(ethoxycarbonyl)phenyl tosylate,p-anisyl tosylate, p-tert-butylphenyl tosylate, o-methylphenyl tosylate,o-anisyl tosylate, p-chlorophenyl tosylate, parabenzophenonyl tosylate,p-formylphenyl tosylate, 2-methylcyclohexenyl tosylate,2-methylbenzo[d]thiazol-5-yl tosylate, 1-tosyl-lH-indol-5-yl tosylate,m-anisyl tosylate, p-(trifluoromethyl)phenyl tosylate, andp-fluorophenyl tosylate, 1-naphthyl triflate, 2-naphthyl triflate,phenyl triflate, p-(ethoxycarbonyl)phenyl triflate, p-anisyl triflate,p-tert-butylphenyl triflate, o-methylphenyl triflate, o-anisyl triflate,p-chlorophenyl triflate, parabenzophenonyl triflate, p-formylphenyltriflate, 2-methylcyclohexenyl triflate, 2-methylbenzo[d]thiazol-5-yltriflate, 1-tosyl-lH-indol-5-yl triflate, m-anisyl triflate,p-(trifluoromethyl)phenyl triflate, and p-fluorophenyl triflate,2-thienyl and 3-thienyl triflates and their benzoderivatives, 2-furanyland 3-furanyl triflates and their benzoderivatives, N-Boc-2-pyrrolidinyland N-Boc-3-pyrrolidinyl triflates, cyclohexenyl triflate, 1-styryl and(E)-2-styryl triflates. Other traditional Heck cross-coupling partners(e.g. mesylates) and non-traditional Heck cross-coupling partners (e.g.alkyl halides, triflates, tosylates, etc.) are known to those ofordinary skill and may also be suitable reaction partners in thedisclosed method.

The aryl halide comprises an optionally substituted aryl group which maycomprise the aforementioned substituents. Preferably, the aryl group isphenyl. In a preferred embodiment, the substituents areelectron-donating groups such as amino, alkoxyl, and alkyl. In anotherpreferred embodiment, the substituents are electron-withdrawing groupssuch as nitro, cyano, and acetyl. The aryl group may comprise up to 5substituents. Preferably, there is one substituent. The substituent maybe located ortho, meta, or para to the halogen atom. Preferably, thesubstituent is located para to the halogen atom.

The aryl halide may be an aryl monohalide such as aryl chloride, arylbromide, and aryl iodide. Preferably, the aryl monohalide is an aryliodide such as iodobenzene. Exemplary aryl monohalide includes, withoutlimitation, iodobenzene, 4-iodoaniline, 4-iodoacetophenone,4-iodobenzonitrile, 4-iodoanisole, bromobenzene, 4-bromoacetophenone,and 1-iodo-4-nitrobenzene.

In another embodiment, the aryl halide is an aryl dihalide such as1,4-dichlorobenzene, 1,4-dibromobenzene, and 1,4-diiodobenzene.Preferably, the aryl halide is 1,4-diiodobenzene.

The acrylic acid or derivatives thereof may have the followingstructure:

where each of R₈ and R₉ is H, an optionally substituted alkyl group, anoptionally substituted aryl group, or the aforementioned substituents.The optionally substituted alkyl group may comprise 3-20 carbon atoms,preferably 4-15 carbon atoms, more preferably 6-12 carbon atoms. Theoptionally substituted alkyl group may be substituted with theaforementioned substituents such as cyano, halo, hydroxyl, silane andderivatives thereof, silyl ether and derivatives thereof, phenethyl, andphenylpropyl. The optionally substituted aryl group may be a phenylgroup. The optionally substituted aryl group may be substituted with theaforementioned substituents such as amino, trifluromethyl, and formyl.In some embodiments, derivatives of acrylic acid include, withoutlimitation, acrylate (e.g. sodium acrylate, zinc acrylate, zirconiumacrylate, and potassium acrylate), acrylate esters (e.g. methacrylate,ethyl acrylate, n-propyl acrylate, n-butyl acrylate, n-pentyl acrylate,n-hexyl acrylate, 2-carboxyethyl acrylate, 2-(dimethylamino)ethylacrylate, 1,1,1,3,3,3-hexafluoroisopropyl acrylate, isobornyl acrylate,ethylene glycol methyl ether acrylate, hydroxypropyl acrylate, laurylacrylate, t-butyl acrylate, isooctyl acrylate, octadecyl acrylate,tetrahydrofurfuryl acrylate, di(ethylene glycol) 2-ethylhexyl etheracrylate, 1H,1H,2H,2H-perfluorodecyl acrylate, (E)-methyl3-(1H-pyrazolo[3,4-b]pyridin-5-yl)acrylate, isodecyl acrylate, tridecylacrylate, 4-tert-butylcyclohexyl acrylate, 2,2,3,3,3-pentafluoropropylacrylate, 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl acrylate,2,2,3,3,4,4,4-heptafluorobutyl acrylate,2,2,3,3,4,4,5,5,6,6,7,7-dodecafluoroheptyl acrylate,2,2,3,3,4,4,5,5-octafluoropentyl acrylate,3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,12-heneicosafluorododecylacrylate, 3,5,5-trimethylhexyl acrylate, 2,2,3,4,4,4-hexafluorobutylacrylate, 4-hydroxybutyl acrylate, octyl acrylate, 2-naphthyl acrylate,2-chloroethyl acrylate, decyl acrylate, 4-acetoxyphenethyl acrylate,2-ethylhexyl ester acrylate, 2-hydroxy-3-phenoxypropyl acrylate,3-(dimethylamino)propyl acrylate, 10-undecenyl acrylate,2-tetrahydropyranyl acrylate, behenyl acrylate, pentafluorophenylacrylate, 2,2,2-trifluoroethyl acrylate), acrylamide,N-(hydroxymethyl)acrylamide, diacetone acrylamide, N-hydroxyethylacrylamide, N-(isobutoxymethyl)acrylamide,N-(3-methoxypropyl)acrylamide, N-[tris(hydroxymethyl)methyl]acrylamide,N-(1,1,3,3-tetramethylbutyl)acrylamide,7-[4-(trifluoromethyl)coumarin]acrylamide, 3-(4-methylphenyl)acrylamide,N-(t-butyl)acrylamide. When R₉ is a substituent other than hydrogen, theelectrophile in the Heck coupling reaction is an acrylic ester, which isa derivative of acrylic acid. Additional derivatives of acrylic acid canalso be used, such as an acrylamide, wherein —OR₉ in the above formulais replaced with —NR₉R₉.

Using the Mizoroki-Heck reaction, important compounds, such as cinnamicacid and derivatives thereof (e.g. cinammic esters or amides), can besuccessfully prepared. Cinnamic acid and derivatives thereof have beenclassified as anti-cancer agents and have been used in flavors andperfumes (Prithwiraj De, Michel Baltas, Florence Bedos-Belval, CurrentMedicinal Chemistry, 2011, 18, 1672-1703, incorporated herein byreference in its entirety). They belong to the class of auxin, which isrecognized as plant hormones regulating cell growth and differentiation.In addition, cinnamic acid and derivatives thereof have been identifiedas anti-tuberculosis agents (Pere-Joan Cardona, “UnderstandingTuberculosis—New Approaches to Fighting against Drug Resistance; Chapter15: Cinnamic Derivatives in Tuberculosis, Published by InTech—Croatia,2012, Page 337, incorporated herein by reference in its entirety).

In a preferred embodiment, the method comprises reacting an aryl halide(preferably aryl iodide) with an acrylic acid or derivatives thereof(preferably methacrylate or acrylamide) in the presence of a solvent, abase (preferably potassium hydroxide), and the solid-supported catalystof formula (II) at a temperature in a range of 35-110° C., therebyforming the cinnamic acid or derivatives thereof.

In some embodiments, prior to the reacting, the method further comprisesan adding step where the solid-supported catalyst is added to theorganic solvent, followed by the reactants, the base, and water to forma reaction mixture. In another embodiment, the base is first dissolvedin water to form a basic solution, which is then added to the othercompounds in the organic solvent. In one embodiment, the solid-supportedcatalyst is not preformed but is formed in situ in a reaction flask(i.e. at least one of the aforementioned palladium(II) salts and thesolid-supported ligand are added to the reaction flask separately).Preferably, the adding step is performed in air. In another embodiment,the adding step is performed in an inert atmosphere provided by an inertgas such as argon, nitrogen, helium, or mixtures thereof.

The solvent may comprise 5-95% by volume of water and 5-95% by volume ofan organic solvent, based on a total volume of the solvent. Preferably,the solvent comprises 30-70% by volume of water and 30-70% by volume ofan organic solvent, based on the total volume of the solvent. Mostpreferably, the solvent consists of 50% by volume of water and 50% byvolume of the organic solvent, based on the total volume of the solvent.Preferably, deionized distilled water is used. Preferably, the organicsolvent is dimethyl formamide.

The aryl halide is the limiting reagent in the coupling reaction. Anamount of the aryl halide may be in a range of 0.5-20 mmol, preferably0.5-10 mmol, more preferably 0.5-5 mmol. An amount of the acrylic acidor derivatives thereof may be in a range of 0.5-100 mmol, preferably0.5-50 mmol, more preferably 0.5-25 mmol, or 1-5 molar equivalents,preferably 1-3 molar equivalents, more preferably 1-2 molar equivalentsof the amount of aryl halide. An amount of the base may be in a range of0.5-100 mmol, preferably 0.5-50 mmol, more preferably 1-25 mmol, or 1-5molar equivalents, preferably 1-3 molar equivalents, more preferably 2-3molar equivalents of the amount of aryl halide.

An amount of the solid-supported catalyst may range from 0.05-10 mol %of a number of moles of the aryl halide, more preferably 0.2-2 mol %,more preferably 0.2-1 mol %. Although higher catalyst loadings (e.g. upto 20 mol %, 30 mol %, 40 mol %, 80 mol %) may be used and the methodwill still proceed as intended.

The reacting may be performed at a temperature in a range of 35-110° C.,preferably 50-110° C., more preferably 70-100° C. An external heatsource, such as a water bath or an oil bath, an oven, microwave, or aheating mantle, may be employed to heat the reaction mixture. In apreferred embodiment, the external heat source is a thermostattedthermocirculator. In one embodiment, the aqueous solution is not heatedwith microwave irradiation. Preferably, the reacting is performed inair. In another embodiment, the reacting is performed in an inertatmosphere provided by the aforementioned inert gases.

A duration of the reaction may range from 0.5-24 hours, preferably 1-12hours, more preferably 4-8 hours. The reaction may be shaken/stirredthroughout the duration of the reaction by employing a rotary shaker, amagnetic stirrer, or an overhead stirrer. In another embodiment, thereaction mixture is left to stand (i.e. not stirred). In one embodiment,the reaction mixture is preferably mixed in a centrifugal mixer with arotational speed of at least 500 rpm, preferably at least 800 rpm, morepreferably at least 1,000 rpm, even though it can also be mixed with aspatula. In one embodiment, the reaction mixture is sonicated during themixing.

The reaction mixture is preferably heterogeneous and comprises suspendedsolid-supported catalyst particles in the liquid reaction mixture. Inone embodiment, the solid-supported catalyst particles are dispersedwithin the reaction mixture, and may further be filtered and recycled atthe end of the reaction. In one embodiment, the solid-supported catalystis placed in a bag and the bag is immersed in the reaction mixture.Accordingly, the solid-supported catalyst remains in the bag until thecoupling reaction is completed.

The progress of each reaction may be monitored by methods known to thoseskilled in the art, such as thin layer chromatography, gaschromatography, nuclear magnetic resonance, infrared spectroscopy, andhigh pressure liquid chromatography combined with ultraviolet detectionor mass spectroscopy. Preferably, thin layer chromatography and gaschromatography combined with mass spectroscopy are used.

Under the basic reaction conditions, cinnamate (instead of cinnamicacid) and derivatives thereof may be obtained. The cinnamate andderivatives thereof may be converted to the acid form by adding amineral acid (e.g. hydrochloric acid, sulfuric acid, and phosphoricacid) during the reaction work up.

The compounds obtained by the method of the present disclosure areisolated and purified by employing the aforementioned methods which arewell-known to those skilled in the art. The isolated yield of thecinnamic acid or derivatives thereof is at least 80%, preferably atleast 90%, more preferably at least 92%, based on the initial number ofmoles of the aryl halide. The cinnamic acid or derivatives thereof,resulting either from a single run or a combination of runs, comprisesless than 10 ppb palladium (measured by ICP-MS), preferably less than 5ppb, more preferably less than 1 ppb, based on a total weight of thecinnamic acid or derivatives thereof.

In some embodiments, the method further comprises separating thesolid-supported catalyst from the cinnamic acid or derivatives thereof,followed by recycling the used solid-supported catalyst. Thesolid-supported catalyst may be separated by removing the bag ofsolid-supported catalyst, dialysis in a solvent, or using a micro-filteror a paper filter.

The phrase “recycling the solid-supported catalyst” refers to a processwhereby the solid-supported catalyst is first washed by an organicsolvent, dried, and then added to a new batch of reactants (either forthe same or a different type of coupling reaction). Preferred organicsolvents for washing the solid-supported catalyst and/or dialysis mayinclude, without limitation, methanol, acetone, ethanol,tetrahydrofuran, acetonitrile, dichloromethane, ether, glycol ether,acetamide, dimethyl acetamide, dimethyl sulfoxide, or combinationsthereof. The solid-supported catalyst may be dried in vacuum, and/orwith heating, for example, the catalyst may be dried in a vacuum oven.Dried solid-supported catalyst may be stored in a desiccator until thenext run.

In one embodiment, the solid-supported catalyst is recycled for at least2 runs, preferably at least 10 runs, more preferably at least 20 runs,even more preferably at least 30 runs. The catalyst may lose less than 5wt %, preferably less than 2 wt %, more preferably less than 0.1 wt % ofpalladium (based on an initial amount of palladium present in thesolid-supported catalyst) after the solid-supported catalyst is used forat least 2 runs, preferably at least 10 runs, more preferably at least20 runs, even more preferably at least 30 runs. The yield of thecoupling reaction may decrease less than 20 percentage points,preferably less than 10 percentage points, more preferably 5 percentagepoints after the solid-supported catalyst is used for at least 2 runs,preferably at least 10 runs, more preferably at least 20 runs, even morepreferably at least 30 runs. The turnover number and the turnoverfrequency of the solid-supported catalyst may decrease less than 10%,preferably less than 5%, more preferably less than 2% after thesolid-supported catalyst is used for at least 2 runs, preferably atleast 10 runs, more preferably at least 20 runs, even more preferably atleast 30 runs.

Having generally described this disclosure, a further understanding canbe obtained by reference to certain specific examples which are providedherein for purposes of illustration only and are not intended to belimiting unless otherwise specified.

Example 1 Reagents and Experimental Methods

Materials for the synthesis of the solid-supported ligand and palladiumcomplex were purchased from Sigma-Aldrich and were used as received. Allsolvents used in the synthesis were distilled before their use. 4-Benzylchloride functionalized silica gel (200-400 mesh, extent of labelling:1.2 mmol/g loading) was purchased from Sigma-Aldrich.

Solid state NMR spectral data was recorded using CP-MAS on a BrukerAvance 400 MHz machine. IR spectra were recorded in wavenumbers (cm⁻¹)using FT-IR spectrometer (Perkin-Elmer 16F model). Elemental analyseswere performed on Perkin Elmer Series 11 (CHNS/O) Analyzer 2400.Palladium loading was estimated using inductively coupled plasma massspectrometer, X-series 2 ICP-MS, thermos scientific. Thermal stabilityof the solid-supported ligands and complexes were established usingthermogravimetric (TG) (Perkin-Elmer TGA 7, US) analysis at a heatingrate of 10° C. min⁻¹ through to 700° C. under nitrogen atmosphere. Themorphology of the supports, solid-supported ligands and solid-supportedcomplexes were studied using scanning electron microscope, JEOLJSM6610LV SEM.

Example 2 Synthesis of Precursor to Ligand,2,2′-(4-Iodobenzene-1,2-diyl)-bis(4,4-dimethyl-4,5-dihydro-1,3-oxazole)(BOX-1)

The precursor to the ligand was prepared using an earlier publishedprocedure (M. B. Ibrahim, B. El Ali, M. Fettouhi, L. Ouahab, Appl.Organometal. Chem, 2015, 29, 400, incorporated herein by reference inits entirety). A solution of 4-iodophthalonitrile (4.0 mmol) and zinctriflate (5.0 mol %, 0.2 mmol) in dried chlorobenzene (30 mL) wasstirred at room temperature for 15 minutes. A solution of2-amino-2-methyl-1-propanol (8.0 mmol) in dry chlorobenzene (5 mL) wasslowly added. The temperature was raised to 135° C. and the reactionmixture was refluxed for 24 hours. The solvent was removed using arotary evaporator. The crude product was dissolved in 30 mL ofdichloromethane and extracted twice with distilled water (2×20 mL). Theaqueous layer was then separated and the combined organic layers weredried with anhydrous sodium sulfate. The dichloromethane was removedusing a rotary evaporator to obtain the impure product, which was thenpurified using silica gel column chromatography withdichloromethane/ether (4/1) as eluent.

Example 3 Synthesis of Hydroxyl Functionalized bis(oxazoline) Ligand,3,4-bis(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)biphenyl-4-ol (BOX—OH)

The synthesis of hydroxyl functionalized BOX ligand (BOX—OH) has beenpreviously described (U.S. provisional patent application 62/313,849,incorporated herein by reference in its entirety).

2,2′-(4-Iodobenzene-1,2-diyl)-bis(4,4-dimethyl-4,5-dihydro-1,3-oxazole)(BOX-1) (0.50 mmol), PdCl₂ (0.025 mmol, 5.0 mol %), K₂CO₃ (1.0 mmol, 2.0mol equivalent), DMF (2 mL), distilled water (2 mL) and the 4-hydroxyphenylboronic acid (0.6 mmol), were added in a 10 mL round bottom flask.The mixture was stirred at 70° C. for 6 h. After completion of thereaction, the mixture was cooled down and acidified with 1M HCl. Theacidified solution was extracted 3 times with EtOAc and the combinedEtOAc extract was dried using anhydrous MgSO₄. The solvent was removedunder reduced pressure and the product was purified by silica gel columnchromatography using hexane-EtOAc (1:9) as an eluent.

Example 4 Synthesis of Solid-Supported bis(oxazoline) Ligand (BOX—Si)

BOX—OH reacted with the benzyl silica support to form the silicaimmobilized BOX ligand (BOX—Si).

NaH (0.50 mmol) was added in one portion to a stirred solution of3,4-bis(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)biphenyl-4-ol (BOX—OH)(0.31 mmol) in dry DMF in a dry flask. The mixture was stirred for 2 hat room temperature and under argon atmosphere. The benzyl silicasupport (0.30 mmol) was added and the mixture was stirred at 90° C. for12 h. The solid product was filtered and washed successively withmethanol, water, acetone and dichloromethane. The product, benzylsilica-supported BOX ligand (BOX—Si), was dried at room temperatureunder vacuum.

It is worth mentioning that the ether bond was considered stable andsuitable for linking the ligand to the silica support. Whereas mostfunctional groups such as esters and amides can easily be hydrolyzedunder the standard conditions of coupling reactions, which involves theuse of bases such as KOH and K₂CO₃ and also heat. The ether linkage isparticularly stable to the reaction conditions and thus, expected toprevent leaching of the ligand during the catalytic application.

Example 5 General Procedure for the Synthesis of Benzyl Silica-Supportedpalladium(II) bis(oxazoline) Catalyst (Pd-BOX—Si)

The silica immobilized BOX ligand was further reacted withbis(benzonitrile) palladium(II) chloride to produce the silica-supportedpalladium(II)-bis(oxazoline) catalyst (Pd-BOX—Si).

The silica-supported bis(oxazoline) ligand (BOX—Si) (0.30 mmol, 0.25 g)was stirred in anhydrous toluene for 30 min. A solution ofbis(benzonitrile) palladium(II) chloride (0.30 mmol, 0.12 g) in toluenewas added and the resulting mixture was stirred at 90° C. for 12 h. Thesolid product, benzyl silica-supported palladium(II) bis(oxazoline)catalyst (Pd-BOX—Si), was filtered, washed thoroughly with ethanol anddried in a vacuum.

The metal loading of the solid-supported palladium catalyst, which wasdetermined using ICP-MS, was found to be 2.8% and equivalent to 0.30mmol/g. The palladium loading of the silica-supporteddichloridopalladium(II) bis(oxazoline) catalyst was determined usingICP-MS and was found to be 2.8%. This corresponds to 0.3 mmol palladiumper gram of the solid-supported catalyst.

The formation of Pd-BOX—Si was confirmed by Fourier transform infraredspectroscopy (FT-IR), solid-state cross-polarization magic anglespinning carbon-13 nuclear magnetic resonance (CP-MAS ¹³C NMR),elemental analysis and inductively coupled plasma mass spectrometry(ICP-MS). The Pd-BOX—Si was further characterized with scanning electronmicroscopy (SEM) and thermogravimetric analysis (TGA).

Example 6 Characterization of Silica-Supported bis(oxazoline) Ligand(BOX—Si) and palladium(II) (Pd-BOX—Si) Catalyst Using FT-IR

FT-IR analysis of the silica-supported bis(oxazoline) ligand reveals astrong band at 1661 cm⁻¹ (FIG. 1). This band was initially absent in theunmodified benzyl silica support (FIG. 1). This band reflects —C═N—stretching in the oxazoline ring. The appearance of this additional bandis an indication that the BOX ligand has been incorporated into thesilica support matrix. The —C═N— stretching band shifted to 1643 cm⁻¹ oncomplexation with palladium (FIG. 1).

Example 7 Characterization of Silica-Supported BOX Ligand (BOX—Si) andpalladium(II) (Pd-BOX—Si) Catalyst Using CP-MAS ¹³C NMR

The silica-supported ligand and palladium(II) complex were furthercharacterized using solid state ¹³C NMR. The spectra of the silica boundligand (FIG. 2) and its palladium(II) complex (FIG. 3) were in entireagreement with those reported for other known bis(oxazoline) andsolid-supported bis(oxazoline) ligands and their complexes. Forinstance, the resonance due to imino carbon (—C═N) was observed at169.96 ppm in the spectrum of the silica-supported ligand. This bandslightly shifted to 170.63 ppm after complexation. The CP-MAS spectra ofboth the solid-supported ligand and complex showed that the signals forthe carbon atoms of the two bis(oxazoline) rings are no longer symmetriccomparing to the free ligand and complex.

Example 8 Analysis of Silica-Supported palladium(II)-BOX (Pd-BOX—Si)Catalyst Using TGA

The thermal stability for the palladium(II) catalyst (Pd-BOX—Si) wasdetermined using TGA (FIG. 4). The Pd-BOX—Si was found to possess highthermal stability with a decomposition temperature of 150° C.

Example 9 Analysis of Silica-Supported BOX Ligand (BOX—Si) andpalladium(II) (Pd-BOX—Si) Catalyst Using SEM

In order to assess the morphology of the 4-benzyl chloridefunctionalized silica support, the silica-supported BOX ligand andpalladium(II) catalyst, SEM micrographs were recorded for a pure benzylchloride silica support, silica-supported bis(oxazoline) ligand (BOX—Si)and silica-supported palladium(II)-bis(oxazoline) catalyst (Pd-BOX—Si).As expected, the smooth and flat surfaces of the 4-benzyl chloridefunctionalized silica support (FIG. 5), have been broken to a rough andirregular surface after incorporation of the metal complex (FIG. 7)(Trilla, M.; Pleixats, R.; Wong Chi Man, M.; Bied, C.; Moreau, J. J. E.Tetrahedron Lett. 2006, 47, 2399; Trilla, M.; Pleixats, R.; Wong ChiMan, M.; Bield, C.; Moreau, J. J. E. Adv. Synth. Catal. 2008, 350, 577;Gruber-Woelfler, H.; Radaschitz, P. F.; Feenstra, P. W.; Haas, W.;Khinas, J. G. J. Catal. 2012, 286, 30; and Antony, R.; Tembe, G. L.;Ravindranathan, M.; Ram, R. N. J. Appl. Polym. Sci., 2003, 90, 370, eachincorporated herein by reference in their entirety).

Example 10 Characterization of Silica-Supported palladium-bis(oxazoline)(Pd-BOX—Si) Catalyst Using X-Ray Photoelectron Spectroscopy (XPS)

In the XPS spectrum of Pd-BOX—Si catalyst (FIG. 8), palladium peaks wereobserved in the range of 335 to 342 eV. Two distinctive 3d peaks wereidentified. The first peak with binding energy of 336.08 eV (Pd3d_(5/2)) and the second peak with binding energy 341.38 (Pd 3d_(3/2)).The data is consistent with palladium(II) forms, and this confirmed thatpalladium(II) is the main form of palladium in the solid-supportedcatalyst (Yeap, H. N; Mian, W.; Hong, H.; Christina, L. L. C. Chem.Commun., 2009, 5530; and Hajipour, A. R.; Shirdashtzade, Z.; Azizi, G.J. Chem. Sci., 2014, 126, 1, 85, each incorporated herein by referencein their entirety).

Example 11 Catalytic Activities of Silica-Supportedpalladium-bis(oxazoline) (Pd-BOX—Si) in Mizoroki-Heck Coupling Reaction

The catalytic activity of the new silica-supportedpalladium-bis(oxazoline) catalyst in Mizoroki-Heck coupling reaction ofvarious olefins and aryl halides was carefully studied. Thecross-coupling reactions of various aryl halides with acrylic acid,methacrylate and acrylamide were considered.

The recycling ability of the new silica-supportedpalladium-bis(oxazoline) catalysts in Mizoroki-Heck coupling reaction ofiodobenzene with methacrylate was investigated (Equation 1 and FIG. 10).Interestingly, the solid-supported catalyst was recycled up to ten timeswithout significant loss in catalytic activity. The turnover number ofthe silica-supported palladium-bis(oxazoline) catalyst was estimated forthe 10 runs as 1800, while the turnover frequency was found to be 300/h.In order to confirm the efficiency of the solid-supportedpalladium-bis(oxazoline) catalyst, an experiment with a ratio ofiodobenzene (10.0 mmol) to solid-supported palladium-bis(oxazoline)catalyst (0.005 mmol) equal to 2,000 was left to react for 6 hours. Acomplete conversion of iodobenzene and excellent isolated yield ofproduct 3aa (93%) was observed. The turnover number of thesolid-supported palladium-bis(oxazoline) catalysts in the laterexperiment was estimated as 1,860, while the turnover frequency wasfound as 310/h.

Example 12 Mizoroki-Heck Coupling Reaction of Various Acrylates withAryl Halides Catalyzed by Silica-Supported palladium-bis(oxazoline)(Pd-BOX—Si) Catalyst

The Mizoroki-Heck coupling of a broad range of substrates using DMF-H₂O(1:1) as a solvent system and KOH as a base (Equation 2) was performed.Thus, various aryl halides including aryl iodides and aryl bromides werecoupled successfully with various with different acrylates (Table 1).The silica-supported catalyst was used in the coupling of aryl halideswith acrylate, acrylic acid and acrylamide. At the end of each reaction,the catalyst was removed from the reaction mixture and dialyzed in DMFto remove all traces of reactants and products before taking it to thenext catalytic run.

The coupling reactions of aryl halides with methacrylate, acrylic acidand acrylamide were investigated (Table 1). Under the reactionconditions, the acrylates and acrylamides were hydrolyzed to thecorresponding salts of the carboxylic acids. The aryl propenoic acidswere obtained after acidic work up. Aryl iodides having eitheractivating or deactivating groups reacted smoothly with acrylates togive the cross coupling products in excellent isolated yields (90-96%)(Table 1, entries 1-7). The coupling reactions of aryl bromides wereconducted at 100° C., using a fresh catalyst and without dialysis bag.Also, high isolated yields of the coupling products were obtained(84-88%) (Table 1, entries 8-10).

TABLE 1 Mizoroki-Heck coupling reactions of acrylates with aryl halidesusing silica-supported palladium bis(oxazoline) (Pd-BOX-Si)catalyst.^(a) Aryl halide Alkene Coupling Product Yield Entry 1 2 3(%)^(b) 1

1a

2a

3aa 91 2 1a

2b

3ab 96 3 1a

2c

3ac 90 4

1b 2a

3ba 91 5 1b 2b

3bb 94 6

1c 2a

3ca 90 7 1c 2b

3cb 93 8^(c)

1d 2a

3aa 84 9^(c) 1d 2b

3aa 80 10^(c)

1e

2b

3eb 88 ^(a)Reaction conditions: [Pd-BOX-Si] (0.0050 mmol), alkene (1.5mmol), aryl halide (1.0 mmol), KOH (2.0 mmol), DMF (3.0 mL), H₂O (3.0mL), 80° C., 6 h, acid workup. ^(b)Isolated yield. ^(c)100° C.

Example 13 Characterization of the Used Solid-Supportedpalladium-bis(oxazoline) Catalysts

The ability to reuse the solid-supported palladium-bis(oxazoline)catalysts several times and in various reactions without significantloss in their catalytic activities demonstrates their high stabilities.The interesting results realized with the solid-supported catalystsurged the inventors to carry out further investigations to asses anychange in the structure of the used catalysts in comparison with theunused catalysts. The catalysts recovered after the 12^(th) run of theSuzuki coupling reaction and the 10^(th) run of both the Mizoroki-Heckand the Sonogashira coupling reactions were washed successively withdistilled water, acetone and methanol. The catalysts were then dried inan oven at 100° C. prior to analysis. The purified catalysts wereanalyzed with FT-IR, XPS and the amount of palladium was establishedusing ICP-MS.

Example 14 Characterization of the Used Silica-Supportedpalladium-bis(oxazoline) (Pd-BOX—Si) Catalyst Using FT-IR

The catalyst was pressed into pellets with KBr and analyzed using FT-IR.The FT-IR spectrum for the recovered silica-supportedpalladium-bis(oxazoline) (Pd-BOX—Si) (FIG. 1) catalyst was found to besimilar with the spectrum of the unused (fresh) catalyst.

Example 15 Analysis of the Used Silica-Supportedpalladium-bis(oxazoline) (Pd-BOX—Si) Catalyst Using ICP-MS

The percentage of palladium on Pd-BOX—Si recovered from theMizoroki-Heck coupling reaction of iodobenzene with methacrylate wasfound to be 2.4%, which is similar to the amount of palladium on thefresh catalyst (2.8%). This result further justifies the high recyclingability observed with the new silica-supported palladium-bis(oxazoline)catalyst.

Example 16 Analysis of the Used Solid-Supported palladium-bis(oxazoline)Catalysts Using XPS

The XPS spectra of the used silica-supported palladium-bis(oxazoline)catalyst (Pd-BOX-13) (FIG. 9) recovered after the tenth run of theMizoroki-Heck coupling reaction showed that the oxidation state ofpalladium remained unchanged after the catalysis. Similar to the unused(fresh) solid-supported catalysts, the 3d spectrum resolved into3d_(5/2) and 3d_(3/2) spin orbit pairs with binding energies 334.58 eVand 339.78 eV (Pd-BOX—Si) and 336.18 and 341.68 (Pd-BOX-13)respectively.

Example 17 Palladium Leaching Test

The main objective of supporting a catalyst is to ease its separationfrom the product and to minimize the level of contamination caused bythe toxic metal. The leaching of palladium into the products wasanalyzed using ICP-MS. After the tenth run of the Mizoroki-Heck couplingreaction, a sample from each run of the coupling reaction was taken forthe analysis and digested using concentrated nitric acid. In addition,the products of the 10 runs were combined, digested using concentratednitric acid. All samples were analyzed by ICP-MS.

The results of the ICP-MS analysis indicated that the concentration ofpalladium in the combined products was below 10 ppb. These resultsindicated that less than 0.5% of the total palladium on thesolid-supported catalysts was leached into the products. These resultsclearly indicated the high stability of the solid-supported catalyststowards the cross-coupling reactions under the prescribed reactionconditions.

1-8. (canceled)
 9. A method for synthesizing cinnamic acid, the methodcomprising: reacting an aryl halide with an acrylic acid in the presenceof a solvent, a base, and a solid-supported catalyst of formula (II) ata temperature in a range of 35-110° C., thereby forming the cinnamicacid:

wherein Si is a solid silica support.
 10. The method of claim 9, furthercomprising: separating the solid-supported catalyst from the cinnamicacid; and reusing the solid-supported catalyst in at least two cycles,wherein the solid-supported catalyst loses less than 5 wt % of thepalladium after the at least two cycles.
 11. The method of claim 9,wherein the aryl halide is a limiting reactant.
 12. The method of claim9, wherein an amount of the solid-supported catalyst is in a range of0.05-10 mol % relative to a number of moles of the aryl halide.
 13. Themethod of claim 9, wherein the solvent comprises 5-95% by volume ofwater and 5-95% by volume of an organic solvent, based on a total volumeof the solvent. 14-19. (canceled)